The nasal cavity in mammals houses distinct chemosensory epithelia including the main olfactory epithelium, the vomeronasal epithelium and the trigeminally innervated respiratory epithelium (so-called "non- sensory" epithelium) (Finger et al., 2000). Each of these receptive epithelia is implicated in detection of diverse compounds and evokes different behaviors. Traditionally, the vomeronasal epithelium was thought to detect pheromones - chemicals released by a conspecific that elicit a physiological or behavioral response in the recipient - while the main olfactory epithelium was thought to mediate conscious perception of general odorants. In addition, the trigeminal system is thought to detect potentially noxious substances, which can elicit aversive responses such as a decrease in respiratory rate, sneezing or coughing. However, recent experiments - including those published by us in the current period of support - indicate that the traditional view on the role of these chemosensory systems needs to be revised because the main olfactory epithelium also appears to be involved in detecting pheromones and other semiochemicals - odors involved in animal communication (Baxi et al., 2006; Buck, 2005; Lin et al., 2007; Lin et al., 2004). This novel aspect of chemoreception by the main olfactory system will be studied in this proposal. We will focus our proposal on our finding that the transient receptor channel M5 (TRPM5), an effector in the phospholipase C (PLC) pathway, is expressed in a subset of olfactory sensory neurons in the main olfactory epithelium whose axons project to semiochemical-responsive glomeruli (Lin et al., 2007). We propose three specific aims: Aim 1. Test whether the PLC pathway participates in olfactory transduction by opening the TRPM5 channel in response to the increase in calcium elicited by odors. Aim 2. Test the hypothesis that sensory input to the nose during the postnatal period affects TRPM5 expression in OSNs Aim 3. Test whether TRPM5 OSNs transmit information about semiochemicals to restricted areas of the MOB which project in turn to the medial amygdala - an area associated with reproductive and defensive behaviors. In humans, disorders of the sense of smell are encountered in diseases such as Alzheimer's (Doty, 1991;Rawson, 2000), bipolar depression (Hahn et al., 2005) and schizophrenia (Turetsky et al., 2003). This grant will study the basic mechanisms of olfactory transduction in olfactory sensory neurons as well as central projections of the olfactory system. This basic science study is performed within the context of the Rocky Mountain Taste and Smell Center (RMTSC), an entity dedicated to basic and clinically-relevant research on olfaction and taste. Drs. Restrepo and Finger are Co-Directors of the RMTSC. Clinically relevant work within the center includes work on schizophrenia, Downs syndrome and brain inflammation. The clinical studies benefit greatly from solid basic science research, and because of this we expect our current proposal to strengthen the clinically relevant work carried out by the RMTSC. Reference List Doty,R.L. (1991). Olfactory dysfunction in neurodegenerative diseases. In Smell and taste in health and disease, T.V. Getchell, R.L. Doty, L.M. Bartoshuk, and J.B. Snow, Jr., eds. (New York: Raven Press), pp. 735-752. Hahn,C.G., Gomez,G., Restrepo,D., Friedman,E., Josiassen,R., Pribitkin,E.A., Lowry,L.D., Gallop,R.J., and Rawson,N.E. (2005). Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am. J. Psychiatry 162, 616-618. Rawson,N.E. (2000). Human olfaction. In The neurobiology of taste and smell, T.E. Finger, W.L. Silver, and D. Restrepo, eds. (New York: Wiley-Liss), pp. 257-284. Turetsky,B.I., Moberg,P.J., Owzar,K., Johnson,S.C., Doty,R.L., and Gur,R.E. (2003). Physiologic impairment of olfactory stimulus processing in schizophrenia. Biol. Psychiatry 53, 403-411. [unreadable] [unreadable] [unreadable]